Key result
Simulated HCM-linked tropomyosin mutations predict increased contractility and diastolic tension via diminished cooperative inhibition.
Computational modeling of HCM-linked tropomyosin mutations reveals a common twitch phenotype characterized by increased contractility and elevated diastolic tension.
Remains hypothesis-generating in animal models; extends computational insights into HCM mutation effects on diastolic tension.
Point mutations to the human gene TPM1 have been implicated in the development of both hypertrophic and dilated cardiomyopathies. Such observations have led to studies investigating the link between single residue changes and the biophysical behavior of the tropomyosin molecule. However, the degree to which these molecular perturbations explain the performance of intact sarcomeres containing mutant tropomyosin remains uncertain. Here, we present a modeling approach that integrates various aspects of tropomyosin's molecular properties into a cohesive paradigm representing their impact on muscle function. In particular, we considered the effects of tropomyosin mutations on (1) persistence length, (2) equilibrium between thin filament blocked and closed regulatory states, and (3) the crossbridge duty cycle. After demonstrating the ability of the new model to capture Ca-dependent myofilament responses during both dynamic and steady-state activation, we used it to capture the effects of hypertrophic cardiomyopathy (HCM) related E180G and D175N mutations on skinned myofiber mechanics. Our analysis indicates that the fiber-level effects of the two mutations can be accurately described by a combination of changes to the three tropomyosin properties represented in the model. Subsequently, we used the model to predict mutation effects on muscle twitch. Both mutations led to increased twitch contractility as a consequence of diminished cooperative inhibition between thin filament regulatory units. Overall, simulations suggest that a common twitch phenotype for HCM-linked tropomyosin mutations includes both increased contractility and elevated diastolic tension.
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Sewanan et al. (2016) studied Hypertrophic cardiomyopathy. Tropomyosin mutations (E180G and D175N) vs. Wild-type tropomyosin was evaluated on Twitch contractility and diastolic tension. Simulations of HCM-linked tropomyosin mutations E180G and D175N predicted increased twitch contractility and elevated diastolic tension due to diminished cooperative inhibition.
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